The present invention relates to a new process for the preparation of antibiotic substances belonging to the cephalosporin class of compounds. More specifically, the present invention relates to a new process for the preparation of cefotaxime, cefetamet, and ceftriaxone sodium. The latter compounds belong to a known class of valuable cephalosporanic antibiotics disclosed, for example, in U.S. Pat. No. 4,098,888 (1978) as well as numerous other patents and other publications. This class of antibiotics is characterized by the presence of an oximino group and a 2-aminothiazolyl heterocyclic ring in the 7-acylamido side-chain attached to the cephalosporin nucleus. This class of compounds is also characterized by suitable substituents at the 3-position of the cephalosporin nucleus. It is known that the oximino group in the 7-acylamido side-chain may have the syn or anti configuration, but that the syn isomers have higher antibiotic activity. See, e.g., U.S. Pat. No. 4,152,432 (1979) and U.S. Pat. No. 4,224,371 (1980).
Conventionally, this class of compounds is prepared by first introducing the suitable substituent into the 3-position of the cephalosporin nucleus, and then attaching the suitable substituent to the nitrogen in the 7-position. Thus, U.S. Pat. No. 4,767,852 (1988) discloses a process for the production of known 2-oximinoacetamido-3-cephem-4-carboxylic acid derivatives, including cefotaxime and ceftriaxone, by acylating 7-amino-3-cephem-4-carboxylic acid derivatives already substituted at the 3-position with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate , the latter often being referred to as MAEM. Similarly, U.S. Pat. No. 5,026,843 (1991) discloses a process for preparing ceftriaxone disodium salt hemiheptahydrate. As the first step in the process disclosed in that patent, 7-aminocephalosporanic acid (7-ACA) already suitably substituted at the 3-position is acylated at the 7-position using MAEM as the acylating agent. Thus, MAEM has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothioazolyl group in the 7-acylamido side-chain.
However, there are certain disadvantages to using MAEM as the acylating agent. In particular, a by-product of this reaction is the toxic compound 2-mercaptobenzothiazole. See, e.g., Chemical Abstracts 111, 19243 p (1989). Therefore, there has been an ongoing search for new acylating agents which are capable of introducing the 2-aminothiazolyl group as part of the 7-acylamido side-chain in good yield, but without producing this toxic by-product.
In Tetrahedron Letters 31, 6481 (1990), Walker, D. G., reports the use of certain thioesters, including 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2)-tritylaminothiazol-4-yl)- 2-methoxyiminoacetate and 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-metho xyiminoacetate, as acylating agents in the synthesis of cefepime sulfate. Yields are reported to be in the range of 54-73% when using the latter thioester, which are far below the yields of 85-97% reported for the production of cefotaxime and ceftriaxone when using MAEM as the acylating agent. See, e.g., Examples 1 and 3 of U.S. Pat. No. 4,767,852 and the Example of U.S. Pat. No. 5,026,843.